Type of paternal sperm exposure before pregnancy and the risk of preeclampsia: A systematic review

Review

article

Type

of

paternal

sperm

exposure

before

pregnancy

and

the

risk

of

preeclampsia:

A

systematic

review

Daniele

Di

Mascio

,

Gabriele

Saccone

,

Federica

Bellussi

,

Amerigo

Vitagliano

,

Vincenzo

Berghella

*

a

DepartmentofMaternalandChildHealthandUrologicalSciences,SapienzaUniversityofRome,Italy

b

DivisionofMaternal-FetalMedicine,DepartmentofObstetricsandGynecology,SidneyKimmelMedicalCollegeofThomasJeffersonUniversity,Philadelphia, PA,USA

c_{DepartmentofNeuroscience,ReproductiveSciencesandDentistry,SchoolofMedicine,UniversityofNaplesFedericoII,Naples,Italy} d

DepartmentofObstetricsandGynecology,Sant'OrsolaMalpighiUniversityHospital,UniversityofBologna,Italy

e

DepartmentofWomenandChildren’sHealth,UnitofGynecologyandObstetrics,UniversityofPadua,Padua,Italy

ARTICLE INFO Articlehistory:

Received3February2020

Receivedinrevisedform26May2020 Accepted29May2020 Availableonlinexxx Keywords: Preeclampsia Sex Sperm Coitus Contraception Barrier ABSTRACT

Objective:Theaimofthissystematicreviewwastoevaluatetheroleofpaternalspermexposurebefore pregnancyontheriskofpreeclampsia.

Studydesign:Thesearchwasconductedusingelectronicdatabasesfrominceptionofeachdatabase throughOctober2019.Reviewofarticlesalsoincludedtheabstractsofallreferencesretrievedfromthe search.Onlystudiesevaluatingexposuretopaternalspermbeforepregnancyontheriskofpreeclampsia inthesubsequentpregnancywereincluded.Exposuregroupwasdefinedassignificantexposureto paternalsperm,eithermeasuredbysexualcohabitation,oralsexhabit,orbyabsenceofbarriermethods. Controlgroupswasdefinedasminimalexposuretopaternalsperm,eithermeasuredbylackofsexual cohabitation or oral sex habit, or byuse of barrier methods. Sperm exposure identifiable before pregnancy thatmay besuspected tomodifytheriskof preeclampsiawasexamined. Theprimary outcomewastheincidenceofpreeclampsia.Subgroupanalysesbyparityandtypeofspermexposure wereplanned.Allanalyseswerecarriedoutusingtherandomeffectsmodel.Thepooledresultswere reportedastheORwith95%confidenceinterval(CI).HeterogeneitywasmeasuredusingI-squared (HigginsI2_).

Results:Sevenstudiesincluding7125pregnantwomenwereincludedinthissystematicreview.Overall, theincidenceofpreeclampsiawassimilarinwomenwithahigheroverallspermexposurecomparedto controls,774/5512(14%)vs220/1619(13.6%);OR1.04,95%CI0.88–1.22,respectively.Theincidenceof preeclampsiawassignificantlyreducedinwomenwithahigheroverallspermexposurewhenincluding onlynulliparouswomen,643/3946(16.1%)vs170/725(23.4%);OR0.63,95%CI0.52to0.76.Significant lowerrateofpreeclampsiawasalsofoundfor12-monthsexualcohabitation,494/3627(13.6%)vs123/ 691(17.8%);OR0.73,95%CI0.59 0.90.Significantlyhigherrateofpreeclampsiawasreportedinwomen notusingbarriermethods,315/1904(16.5%)vs103/962(10.7%);OR1.65,95%CI1.30–2.10. Conclusions:Paternalspermexposureinnulliparouswomenandsexualcohabitation>12monthsbefore pregnancyareassociatedwithadecreasedriskofpreeclampsia.

©2020ElsevierB.V.Allrightsreserved.

Contents

Introduction ... 2

Objective ... 2

Methods ... 2

Searchstrategy ... 2

* Correspondingauthorat:DivisionofMaternal-FetalMedicine,DepartmentofObstetricsandGynecology,ThomasJeffersonUniversity,833ChestnutStreet,FirstFloor, Philadelphia,PA19107,USA.

E-mailaddress:vincenzo.berghella@jefferson.edu(V.Berghella).

https://doi.org/10.1016/j.ejogrb.2020.05.065

0301-2115/©2020ElsevierB.V.Allrightsreserved.

EuropeanJournalofObstetrics&GynecologyandReproductiveBiology251(2020)xxx–xxx

ContentslistsavailableatScienceDirect

European

Journal

of

Obstetrics

&

Gynecology

and

Reproductive

Biology

Studyselection ... 2

Definitionsofspermexposure ... 2

Primaryandsecondaryoutcomes ... 3

Riskofbiasassessment... 3

Dataextraction ... 3

Dataanalysis ... 3

Results ... 5

Studyselectionandstudycharacteristics ... 5

Synthesisofresults ... 5

Comment ... 7

Mainfindings ... 7

Comparisonwithexistingliterature ... 7

Strengthsandlimitations ... 7

Implicationsandconclusion ... 1

Financialsupport ... 1

References ... 1

Introduction

Preeclampsiaisadisorderofpregnancyusuallyassociatedwith new-onsethypertensionandproteinuria,occurringmostoftenafter 20weeksofgestationandfrequentlynearterm,whichcomplicates approximately5–8%ofpregnanciesintheUnitedStates. Preeclamp-sia is associated with short-and long-term consequences for both the fetus, such as intrauterine growth restriction, and the mother, includingsubsequenthypertension, andcardiovascular disorders [1,2].AccordingtotheWorldHealthOrganization,preeclampsiais thesecondglobalcauseofmaternalmortalityafterhemorrhage[3]. Thepathophysiologyofpreeclampsiahasnotbeencompletely elucidatedyetandmanytheorieshavebeenproposedtoexplain the complex mechanisms associated with the disease [1]. Defectiveplacentationhasbeenthemajor,long-standing hypoth-esis,withabnormalremodelingofspiralarteriesandtrophoblastic invasionleadingtoplacentalchronichypoxiaandischemia[4,5], but recent research has reported that an abnormal maternal cardiovascularsystemcouldnotonlybethetriggerofabnormal placentation,butalsoplayacausativeroleinthepathogenesisof thecondition[6–8].Moreover,othermechanismssuchasgenetic imprinting,imbalancesofangiogenicfactorsandimmunological factors have all been considered to be involved in case of preeclampsia[1,4]. The immune maladaptation theoryinvolves amaternalalloimmunereactiontriggeredbyarejectionofthefetal allograftthatcouldbepreventedthroughpaternalspermexposure beforepregnancy,byinitiatingatype-2immuneresponsetowards paternal antigens that may inhibit the induction of type-1 responses against the semi-allogenic fetal unit [1,9]. This hypothesis seems to be confirmed also from evidence of a significantlyincreasedriskofpreeclampsiainin-vitrofertilization (IVF)pregnancies achieved with sperm donor. A meta-analysis including 10,898 women showed that conception using donor sperm was associated with an increased risk of preeclampsia comparedwithusingpaternalsperm[10].

Objective

Theaimofthissystematicreviewwastoevaluatetheroleof paternal sperm exposure before pregnancy on the risk of preeclampsia.

Methods Searchstrategy

Thisreviewwasperformedaccordingtoaprotocoldesigneda priori and recommended for systematic review [11]. Electronic

databases(Medline,Scopus,Embase,WebofSciences,theCochrane library,clinicaltrials.gov)weresearchedfromtheinceptionofeach database to October 2019. Review of articles also included the abstractsofallreferencesretrievedfromthesearch.Norestrictions forlanguageorgeographiclocationwereapplied.

Thearticleswereidentifiedwiththeuseofacombinationofthe relevantheadingterm,keywords,andwordvariantsfor:“sex”OR “coitus”OR“sexualrelationship”OR“sexualcohabitation”OR“oral sex”OR“contraception”OR“condom” OR“sperm”OR“seminal fluid”[Mesh/Emtree]AND“preeclampsia”.Theelectronicsearch andtheeligibilityofthestudieswereindependentlyassessedby twooftheauthors(DDM,AV).Amanualsearchofreferencelistsof studies was performed to avoid missing relevant publications. Differenceswerediscussedwithathirdreviewer(VB).

Studyselection

Only studies evaluating exposure to paternal sperm before pregnancyontheriskofpreeclampsiainthesubsequentpregnancy were included. We excluded papers comparing two groups of women whowerebothexposedtospermbeforepregnancy.Onlyfull textarticleswereconsideredeligiblefortheinclusion.Randomized, cohortandcase-controlstudieswereacceptedstudydesigns.

Studieswithoutacontrolgroup(e.g.casereports,caseseries) wereexcluded. Studiesinvestigating theonset of preeclampsia after assisted conception procedures (i.e. in vitro fertilization, intracytoplasmic sperm injection, intra-uterine insemination) werealsoexcluded.

Definitionsofspermexposure

Exposuregroupwasdefinedassignificantexposuretopaternal sperm,eithermeasuredbysexualcohabitation,oralsexhabit,or by absence of barrier methods. Control groups was defined as minimalexposuretopaternalsperm,eithermeasuredbylackof sexualcohabitationororalsexhabit,orbyuseofbarriermethods. Exposure to paternalsperm was self-reportedby women with telephoneorfacetofaceinterviewsandquestionnaires.

Sperm exposure identifiable before pregnancy that may be suspectedtomodifytheriskofpreeclampsiawasexamined.

Weplannedtoanalyzethefollowingspermexposuresbefore pregnancy:

 overallspermexposure(eithersexualcohabitation,oralsexor lackofusebarriermethods);

 sexualcohabitation(12months);

 oralsex(eitherwithorwithoutspermingestion);  lackofuseofbarriermethods.

Primaryandsecondaryoutcomes

Primary and secondary outcomes were defined before data extraction.Theprimaryoutcomewastheincidenceof preeclamp-sia,as defined in theoriginal studies.The secondary outcomes weregestational hypertension(GH), defined as blood pressure valueshigherthan140/90mmHginpre-gestationalnormotensive women,pretermbirth(PTB)atlessthan37weeksofgestation,and perinatal outcomes, including small for gestational age (SGA), definedasbirthweightlowerthan10thpercentileforgestational age, admission to neonatal intensive care unit (NICU), and perinatalmortality.

Riskofbiasassessment

Tworeviewers(DDM,GS)independentlyassessedtheriskof biasoftheincludedstudiesviatheMethodologicalIndexfor Non-RandomizedStudies(MINORS).Sevendomainsrelatedtoriskof biaswereassessedineachstudy:1)Aim(i.e.clearlystatedaim), 2)Rate(i.e.inclusionofconsecutivepatientsandresponserate), 3)Data(i.e.prospectivecollectionofdata),4)Bias(i.e.unbiased assessment of study endpoints), 5) Time (i.e. follow-up time appropriate),6)Loss(i.e.losstofollow-up),7)Size(i.e.calculation ofthestudysize).Reviewauthors’judgmentswerecategorizedas “lowrisk,”“highrisk”or“unclearriskofbias”[12].Discrepancies wereresolvedbydiscussion.

Dataextraction

Data extraction was completed by two independent inves-tigators(DDM,GS).Eachinvestigatorindependentlyextracteddata aboutstudyfeatures,population,andriskfactorsforpreeclampsia. Information of adjusting for confounders and adjusted risk estimates were collected when available. Differences were resolvedbyconsensus.

Dataanalysis

DataanalysiswasperformedwithReviewManagerVersion 5.3(NordicCochraneCentre,CochraneCollaboration,Denmark). Allanalyseswerecarriedoutusingtherandomeffectsmodel(of DerSimonianandLaird,assumingthatthedatabeinganalyzed was drawn from a hierarchy of different populations). The pooled resultswere reportedas the ORwith 95%confidence interval (CI). Heterogeneity was measured using I-squared (HigginsI2_).

Subgroup analyses according to type of paternal sperm exposure, such as sexual cohabitation > 12 months, oral sex, andlackofuseofbarriermethods,wereplannedtoevaluatethe risk of preeclampsia. We also plannedtoevaluate the primary outcomebyparity.

The systematic reviewwas reportedfollowing the Preferred Reporting Item for Systematic Reviews and Meta-analyses

Fig.1.Studyflowchart.

Table 1

General characteristics of the included studies. Andraweera 2018 [14]

Saftlas 2013 [15] Ness 2004 [16] Einarsson 2003 [17]

Verwoed 2002 [18] Koelman 2000 [19]

Klonoff-Cohen 1989 [20] Study Location Australia, UK,

Ireland

USA USA USA South Africa The Netherlands USA

Sample size 277 vs 3334 258 vs 182 85 vs 2126 113 vs 226 110 vs 110 41 vs 44 107 vs 112

Period considered 2004 2011 2002 2005 1997 2001 2000 2001 2000 2001 NR 1984 vs 1987

Type of study Cohort study Case control study Case control study Case control study Case control study Case control study Case control study

Maternal age (mean) 27.7+5.7 vs 28.8+5.4 26.4+0.3 vs 26.4+0.4 26.6+6.0 vs 25.1+6.0 26.3 vs 25.9 20.2+3.0 vs 20.9+4.0 NR NR

Parity Nulliparous Nulliparous Nulliparous and

multiparous Nulliparous and multiparous Nulliparous and multiparous Nulliparous women Nulliparous women Nulliparous women (%) 100 % vs 100 % 100 % vs 100 % NR 60.2 % vs 62.8 % 45.5 % vs 45.5 % 100 % vs 100 % 100 % vs 100 % Definition of sperm exposure Sexual relationship > 12 months Sexual cohabitation > 12 months; oral sex before pregnancy No barrier methods at 6 month or less before pregnancy No barrier methods; sexual cohabitation >12 months No barrier methods at 6 month or less before pregnancy

Oral sex before pregnancy

No barrier methods before pregnancy Control group Sexual relationship

< 12 months Sexual cohabitation < 12 months; no oral sex before pregnancy Barrier methods at 6 month or less before pregnancy Barrier methods; sexual cohabitation < 12 months Barrier methods at 6 month or less before pregnancy

No oral sex before pregnancy Barrier methods before pregnancy Definition of PE Systolic BP 140 mmHg and/or diastolic BP 90 mmHg on two or more measurements 6 h apart after 20 weeks of gestation with proteinuria (24-h urinary protein 300 mg or spot urine protein: creatinine ratio30 mg/mmol creatinine or urine dipstick protein  2+) or any multisystem complication of PE Systolic BP 140 mmHg and/or diastolic BP 90 mmHg on two or more measurements 6 h apart after 20 weeks of gestation with proteinuria (24-h urinary protein 300 mg or spot urine protein: creatinine ratio30 mg/mmol creatinine or urine dipstick protein  1+) Repeated systolic BP 140 mmHg and/or diastolic BP 90 mmHg and proteinuria>1+ on a catheterized,>2+ on a voided or>300 mg on a 24 h urine specimen, or a protein/creatinine ratio of 0.3 Systolic BP 140 mmHg and/or diastolic BP 90 mmHg on two or more measurements 6 h apart after 20 weeks of gestation with proteinuria (24-h urinary protein 300 mg or spot urine protein: creatinine ratio 30 mg/mmol creatinine or urine dipstick protein  1+)

At least two diastolic BP 90 mmHg taken at least 4 h apart or at least one diastolic BP 110 mmHg and repeated proteinuria of  2+ on dipsticks) Diastolic BP 90 mmHg or more and an increase of at least 20 mmHg compared to the diastolic BP in the first trimester plus proteinuria of at least 300 mg/24 h Systolic BP 140 mmHg and/or diastolic BP 90 mmHg on two or more measurements 6 h apart after 20 weeks of gestation with repeated proteinuria > 300 mg and edema of the face or hands of > 1 = or a gain of > 5 lb in 1 week Main outcome Adverse obstetrical

outcomes

PE PE PE PE PE PE

NR, not reported; BP, blood pressure; PE, preeclampsia. Data are presented as women affected by preeclampsia (cases) vs normotensive women (controls).

D. Di Mascio et al. / European Journal of Obstetrics & Gynecology and Repr oductive Biology 25 1 (2020) xxx – xxx

(PRISMA) statement [13]. The study was registered with the PROSPEROdatabase(registrationnumberCRD42020148320). Results

Studyselectionandstudycharacteristics

Fig.1showstheflowdiagramofinformationderivedfromour review of potentially relevant articles (Fig. 1, Supplementary

Table1).Sevenstudies[14–20]including7125pregnantwomen were included in this systematic review. The majority of the includedwomenwerenulliparous,althoughthreestudies[16_–18] alsoincludedmultiparouswomen(Table1).Spermexposurewas defined as: sexualcohabitation >12 months[14];either sexual cohabitation>12monthsororalsexbeforepregnancy[15];either sexual cohabitation >12 months or no useof barrier methods beforepregnancy[17];nouseofbarriermethodsbeforepregnancy [16,18,20];oralsexbeforepregnancy[19].

Thequalityofthestudiesincludedinourmeta-analysiswas assessedbytheMINORS’toolforassessingtheriskofbias(Fig.2A, B).Allstudieshadlowriskofbiasin“aim,”andthemajorityin “rate”.Six studieswerecase-controlstudiescomparingwomen

affected by preeclampsia with normotensive women [15–20], whileonewasamulticenter,prospectivecohortstudy[14]. Synthesisofresults

Overall,theincidenceofpreeclampsiawas similarinwomen withahigheroverallspermexposurecomparedtocontrols,774/ 5512 (14 %) vs 220/1619 (13.6 %); OR 1.04, 95 % CI 0.88–1.22 (Table2).Theincidenceofpreeclampsiawassignificantlyreduced inwomenwithahigheroverallspermexposurewhenincluding onlynulliparouswomen,643/3946(16.1%)vs170/725(23.4%);OR 0.63,95%CI0.52to0.76(Table3).Conversely,nodifferencewas found when includingonly multiparous women, although this analysiswaslimitedtotwostudies(Table4).

When stratifying according to the type of sperm exposure, significantlylowerrateofpreeclampsiawasfoundfor12-month sexualcohabitation,494/3627(13.6%)vs123/691(17.8%);OR0.73, 95%CI0.59to0.90(Table5),whilenodifferenceswerefoundfor oral sexbeforepregnancy (Table 6).Significantlyhigher rate of preeclampsiawasreportedinwomennotusingbarriermethods, 315/1904(16.5%)vs103/962(10.7%);OR1.65,95%CI1.30–2.10 comparedwiththeotherincludedstudies(Table7)[16,17,18,20].

Fig.2.Assessmentofriskofbias.Aim,clearlystatedaim;Rate,inclusionofconsecutivepatientsandresponserate;Data,prospectivecollectionofdata;Bias,unbiasedassessmentof studyendpoints;Time,follow-uptimeappropriate;Loss,losstofollow-up;Size,calculationofthestudysize.(A)Summaryofriskofbiasforeachstudy.Plussign,lowriskofbias; minussign,highriskofbias;questionmark,unclearriskofbias.(B)Riskofbiasgraphabouteachriskofbiasitempresentedaspercentagesacrossallincluded.

Table 2

Overall effect of sperm exposure on the incidence of PE.

Andraweera 2018 [14] Saftlas 2013 [15] Ness 2004 [16] Einarsson 2003 [17] Verwoed 2002 [18] Koelman 2000 [19] Klonoff-Cohen 1989 [20] TOTAL Exposure No exposure Exposure No exposure Exposure No exposure Exposure No exposure Exposure No exposure Exposure No exposure Exposure No exposure Exposure No exposure OR (95 % CI) PE 228/3092 (7.4 %) 49/519 (9.4 %) 213/364 (58.5 %) 45/76 (59.2 %) 54/1362 (4.0 %) 31/849 (3.7 %) 82/267 (30.7 %) 31/72 (43.1 %) 90/179 (50.3 %) 20/41 (48.8 %) 18/54 (33.3 %) 23/31 (74.2 %) 89/194 (45.9 %) 21/31 (67.7 %) 774/5512 (14.0 %) 220/1619 (13.6 %) 1.04 [0.88 1.22] PE, preeclampsia; OR, odds ratio; CI, confidence interval.

Table 3

Subgroup analysis on nulliparous women.

Andraweera 2018 [14] Saftlas 2013 [15] Einarsson 2003 [17] Verwoed 2002 [18] Koelman 2000 [19] Klonoff-Cohen 1989 [20] TOTAL

Exposure No exposure Exposure No exposure Exposure No exposure Exposure No exposure Exposure No exposure Exposure No exposure Exposure No exposure OR (95 % CI) PE 228/3092 (7.4 %) 49/519 (9.4 %) 213/364 (58.5 %) 45/76 (59.2 %) 51/169 (30.2 %) 17/41 (41.5 %) 35/73 (47.9 %) 15/27 (55.5 %) 18/54 (33.3 %) 23/31 (74.2 %) 89/194 (45.9 %) 21/31 (67.7 %) 634/3946 (16.1 %) 170/725 (23.4 %) 0.63 [0.52 0.76] PE, preeclampsia; OR, odds ratio; CI, confidence interval. Boldface data, statistically significant.

D. Di Mascio et al. / European Journal of Obstetrics & Gynecology and Repr oductive Biology 25 1 (2020) xxx – xxx

Noneofthesecondaryoutcomeswerereportedintheincluded studies.

Comment Mainfindings

The_findingsfromthissystematicreviewshowedthatpaternal spermexposurebeforepregnancyisassociatedwithadecreased riskofpreeclampsiainnulliparouswomen,butnotinallwomen. Significantlowerrateofpreeclampsiawasalsofoundforsexual cohabitation>12months.

Comparisonwithexistingliterature

Thetheoryofpaternalfactorsplayingaroleinthedevelopment ofpreeclampsiaisbasedontheobservationofbothadecreased risk of preeclampsia after prolonged exposure to the paternal seminalfluid[14–20]anda higherincidenceofpreeclampsiain pregnanciesconceivedwithanewfather,leadingtothehypothesis of an immunological role for sperm in producing a mucosal immunetolerance-likestatusattheleveloftheuterusthatcould be significant in the subsequent implantation [21]. These data seemtobesupportedalsobytheevidencethatpreeclampsiaisless commoninnulliparouswomenhavinglongersexualrelationship withthebiologicalfather[22].Similarly,anotherprospectivestudy onthe risk of hypertension in nulliparous women found a 4% decreaseintheriskofdevelopingGHforeverymonthincreasein

sexual cohabitation [23]. In addition, evidence from assisted reproductive technology seemstoshowsimilarassociations, as pregnancies achievedby spermdonorsignificantlyincreasethe risk of preeclampsia [10,24], while pregnancies after double gametedonation areatabout3timeshigherrisk ofdeveloping preeclampsiacomparedwithoocytedonationalone[25]andwith standardIVF[26].

Strengthsandlimitations

There are no other comprehensive, up-to-date systematic reviews exploring the role of paternal sperm exposure before pregnancyontheriskofdevelopingpreeclampsiainthesubsequent pregnancy.Therearealsonoreviewsonthetypeofspermexposure, andanalysisbyparity.Inclusionofnon-randomizedstudies,their retrospective design and smallsamplesize representthe major limitationsofthepresentreview.Theheterogeneityinthebaseline population as well as in the definitionofspermexposure,andthelack ofsomeotherkeyconfounderssuchashistoryofhypertension,body massindex,aspirinuseorethnicitycouldmakeitdifficulttofindan adequate causal link between sperm exposure and subsequent preeclampsia.Moreover,therateofpreeclampsiainbothexposed and not exposed group is higher than usually reported [1,2]. Furthermore,aninherentlimitationofthisstudyisthatinformation aboutspermexposurebeforepregnancywasself-reportedbythe includedwomen-eitherbytelephoneinterview,personalinterview orquestionnaire-leadingtopossiblereportingbiasandrecallbias, potentiallyaffectingourstudyfindings.Finally,thereportedrateof

Table4

Subgroupanalysisonmultiparouswomen.

Einarsson2003[17] Verwoed2002[18] TOTAL

Exposure Noexposure Exposure Noexposure Exposure Noexposure OR(95%CI) PE 31/98(31.6%) 14/31(45.2%) 55/106(51.9%) 5/14(35.7%) 86/204(42.2%) 19/45(42.2%) 1.00(0.52 1.92)

Table5

Subgroupanalysisonsexualcohabitation(>or<12months).

Andraweera2018[14] Saftlas2013[15] Einarsson2003[17] TOTAL

>12months <12months >12months <12months >12months <12months >12months <12months OR(95%CI) PE 228/3092 (7.4%) 49/519 (9.4%) 213/364 (58.5%) 45/76 (59.2%) 53/171 (31.0%) 29/96 (30.2%) 494/3627 (13.6%) 123/691 (17.8%) 0.73[0.59 0.90]

PE,preeclampsia;OR,oddsratio;CI,confidenceinterval.Boldfacedata,statisticallysignificant.

Table6

Subgroupanalysisonoralsex.

Saftlas2013[15] Koelman2000[19] TOTAL

Oralsex Nooralsex Oralsex Nooralsex Oralsex Nooralsex OR(95%CI) PE 217/360(60.3%) 41/80(51.3%) 18/54(33.3%) 23/31(74.2%) 235/414(56.8%) 64/111(57.7%) 0.96[0.63 1.47] PE,preeclampsia;OR,oddsratio;CI,confidenceinterval.

Table7

Subgroupanalysisnobarriervsbarrierusebeforepregnancy.

Ness2004[16] Einarsson2003[17] Verwoed2002[18] Klonoff-Cohen1989[20] TOTAL OR(95%CI) Nobarrier Barrier Nobarrier Barrier Nobarrier Barrier Nobarrier Barrier Nobarrier Barrier

PE 54/1362 (4.0%) 31/849 (3.7%) 82/169 (48.5%) 31/41 (75.6%) 90/179 (50.3%) 20/41 (48.8%) 89/194 (45.9%) 21/31 (67.7%) 315/1904 (16.5%) 103/962 (10.7%) 1.65[1.30 2.10]

PE,preeclampsia;OR,oddsratio;CI,confidenceinterval.

non-paternity(i.e.discrepantbiologicalversussocialfatherhood)of 2–3%couldhaveaffectedourresults[27].

Implicationsandconclusion

Thefindings fromthis systematicreviewhavemanyclinical, ethical, religious and social implications. The evidence that nulliparityissignificantlyassociatedwithhigherriskofdeveloping preeclampsiaiscloselyrelatedtothehypothesisthatnulliparous women have a reduced immune tolerance to paternal sperm antigens, and this is also supported by epidemiological data showinghigherriskofpreeclampsiaassociatedwithanychangein paternity[21].Inourstudy,wefoundasignificantdecreaseinthe rateofpreeclampsiainnulliparouswomenwithlongerexposureto paternalspermandinallwomenreportingsexualcohabitationfor morethan12months.

Inthisreviewasignificantlyhigherrateofpreeclampsiawas foundinnon-barrierusers,comparedtobarrierusers.Thisresult stemsmostlyfrom2studies[17,20]whichhadaveryhighrateof preeclampsia in their small non-barrier groups (Table 7). This findingmayappearsurprisingandincontrastwiththelowerrate ofpreeclampsiareportedinwomenwithsexualcohabitation>12 months.Moreover,apriorIUDusehasbeenshowntobeassociated withanoverallreductionofpreeclampsiathatwashigherwhen removal occurred within one year before pregnancy [28], but persistedevenincaseofpregnanciesconceivedwithIUDinsitu [29,30].Therefore,thechoiceofthemethodforcontraceptionisa complexandpersonalizeddecisionandbasedonthesedata,we cannot advocate for a given method with the sole purpose of decreasingtheriskofpreeclampsiainasubsequentpregnancy.

Weacknowledgethattheseconceptsmightinvolvealsoethical andreligiousissues.Nonetheless,sincethetimeofLeonardoda Vinci, it’s important that scientific researchinforms traditional beliefs, inducing from experiments rather than deducing from theoreticalprinciples[31].

Inconclusion,paternalspermexposureinnulliparouswomen and sexual cohabitation > 12 months before pregnancy are associatedwithadecreasedriskofpreeclampsia.

Financialsupport

Nofinancialsupportwasreceivedforthisstudy DeclarationofCompetingInterest

Theauthorsreportnoconflictofinterest. AppendixA.Supplementarydata

Supplementarymaterialrelatedtothisarticlecanbefound,inthe onlineversion,atdoi:https://doi.org/10.1016/j.ejogrb.2020.05.065. References

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